Research ArticleExperimental Studies
Open Access

Recombinant Methioninase Synergistically Reverses High-docetaxel Resistance Developed in Osteosarcoma Cells

SEI MORINAGA, QINGHONG HAN, KOHEI MIZUTA, BYUNG M. KANG, MICHAEL BOUVET, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, HIROYUKI TSUCHIYA, SATORU DEMURA and ROBERT M. HOFFMAN
Anticancer Research November 2024, 44 (11) 4773-4778; DOI: https://doi.org/10.21873/anticanres.17303

Abstract

Background/Aim: Docetaxel combined with gemcitabine is a second-line therapy for osteosarcoma, but its efficacy is limited by the development of docetaxel resistance. The aim of the present study was to determine whether recombinant methioninase (rMETase) could reverse docetaxel resistance developed in osteosarcoma cells. Materials and Methods: Docetaxel-resistant 143B (DTR-143B) osteosarcoma cells were established by treating the parental 143B cells to increasing docetaxel concentrations (0.14-24 nM) over 5 months. The 50% inhibitory concentration (IC50) of docetaxel and rMETase as well as their combination on human osteosarcoma cells 143B and DTR-143B were determined. Four groups were analysed in vitro: untreated control; docetaxel; rMETase; docetaxel plus rMETase. Results: The IC50 value of docetaxel for DTR-143B cells was 31.1 nM, compared to 4.38 nM for the parental 143B cells, a 7-fold increase. The combination of rMETase (0.53 U/ml) and docetaxel (4.38 nM) sensitized DTR-143B cells to docetaxel resulting in an inhibition of 73.7% compared to docetaxel alone (7.3%) or rMETase alone (54.6%) (p<0.05). rMETase thus increased the efficacy of docetaxel 10-fold on docetaxel-resistant osteosarcoma cells. Conclusion: rMETase reversed docetaxel resistance of DTR-143B in vitro. The present results indicate the clinical potential of rMETase to overcome docetaxel resistance in osteosarcoma patients.

Key Words:

Docetaxel is a semi-synthetic taxane that like other taxanes, induces cellular growth arrest by promoting microtubule assembly and inhibiting disassembly (1). The combination of docetaxel and gemcitabine has recently been used for the treatment of recurrent or refractory osteosarcoma (2). However, the efficacy is limited by the onset of docetaxel resistance. One study showed that 90.4% of patients with refractory metastatic osteosarcoma treated with the combination of docetaxel and gemcitabine had progressive disease due to onset of docetaxel resistance (3). Chemotherapy resistance of osteosarcoma is still a recalcitrant clinical problem resulting in the death of many patients (4, 5).

Methionine restriction of cancer, termed the Hoffman Effect, is a fundamental and universal hallmark of cancer, and is targeted by recombinant methioninase (rMETase) (6, 7). Multiple studies have demonstrated that either rMETase, a methionine-free medium, or a methionine-depleted diet can enhance the effectiveness of chemotherapy due to synergy (8-16).

The present study determined whether rMETase could reverse docetaxel-resistance (DTR) developed in osteosarcoma cells in vitro.

Materials and Methods

Cell culture. 143-B osteosarcoma cells were obtained from the American Type Culture Collection (ATCC) (Manassas, VA, USA). 143B cells were grown in Dulbecco’s modified Eagle’s medium (DMEM) with the addition of 10% fetal bovine serum (FBS) and 1 IU/ml penicillin/streptomycin (10-013-CV; Corning, Corning, NY, USA).

Reagents. Docetaxel was obtained from Accord Healthcare Inc. (Durham, NC, USA). Recombinant methioninase (rMETase) was produced by AntiCancer Inc. as previously described (17).

Establishment of docetaxel-resistant 143B (DTR-143B cells). 143B cells were cultured stepwise in progressively higher concentrations of docetaxel, ranging from 0.14 to 24 nM over a period of five months.

Drug sensitivity assay 1: Calculation of the IC50 of docetaxel and rMETase on 143B and DTR-143B cells. Cell viability was determined with the WST-8 reagent (Dojindo Laboratory, Kumamoto, Japan). 143B and DTR-143B cells were grown in 96-well dishes, with 3×103 cells per well, in DMEM (100 μl per well), and were incubated for several hours. rMETase (0.5 U/ml to 8 U/ml) and docetaxel (4 nM to 64 nM) were added to the cells for 72 h. At the end of the culture period, 10 μl of the WST-8 solution was added to each well. Subsequently, the dish was incubated for 1 h at 37°C. Absorption of the treated cells was measured at 450 nm with a microplate reader (SUNRISE: TECAN, Mannedorf, Switzerland). Microsoft Excel for Mac 2016 version 15.52 (Microsoft, Redmond, WA, USA) was used to generate drug-sensitivity curves. ImageJ version 1.53k (National Institutes of Health, Bethesda, MD, USA) was used to determine half-maximal inhibitory concentrations (IC50) values. Each experiment was conducted twice in triplicate.

Drug sensitivity assay 2: Synergy of docetaxel and rMETase on 143B osteosarcoma cells. 143B cells were seeded in 96-well plates at a density of 3×103 cells per well. Cells were treated as follows 24 h later: Control (DMEM); docetaxel (4.38 nM); rMETase (0.5 U/ml); and docetaxel (4.38 nM) plus rMETase (0.5 U/ml). The viability of the cells was evaluated 72 h later, as described above.

Drug sensitivity assay 3: Synergy of docetaxel and rMETase on DTR-143B osteosarcoma cells. DTR-143B cells were seeded in 96-well plates at 3×103 cells per well. DTR-143B cells were treated as follows: Control (DMEM); docetaxel (4.38 nM); rMETase (0.53 U/ml); and docetaxel (4.38 nM) plus rMETase (0.53 U/ml). The viability of the cells was evaluated 72 h later, as described above.

EZR software (Jichi Medical University, Saitama, Japan) was used for statistical analyses (18). A Tukey–Kramer analysis was used to analyse the relationship between variables. p<0.05 were considered to be statistically significant.

Results

IC50 of docetaxel and rMETase on 143B and DTR-143B cells. The IC50 value of docetaxel on 143B cells was 4.38 nM. The IC50 of docetaxel on DTR-143B cells was 31.1 nM, a seven-fold increase of resistance. The IC50 for rMETase on 143B cells was 0.5 U/ml and the IC50 of rMETase on DTR-143B cells was 0.53 U/ml. These results demonstrate the efficacy on rMETase alone on DTR-143B was similar to rMETase alone on 143B cells (Figure 1).

Figure 1.
Figure 1.

IC50 of docetaxel and recombinant methioninase (rMETase) on 143B and docetaxel-resistant 143B (DTR-143B) cells (mean±SD). (A) Sensitivity of 143B cells to docetaxel. (B) Sensitivity of DTR-143B cells to docetaxel. (C) Sensitivity of 143B cells to rMETase. (D) Sensitivity of DTR-143B cells to rMETase.

Synergy of rMETase and docetaxel on 143B cells. Docetaxel (4.38 nM) plus rMETase (0.5 U/ml) synergistically reduced the viability of 143B cells (p<0.05) (Figure 2).

Figure 2.
Figure 2.

Efficacy of docetaxel, recombinant methioninase (rMETase) and their combination on 143B cells. Control (DMEM); docetaxel (4.38 nM); rMETase (0.5 U/ml); docetaxel (4.38 nM) plus rMETase (0.5 U/ml); n=3, *p<0.05.

rMETase synergistically reversed docetaxel resistance of DTR-143B cells. rMETase (0.53 U/ml) in combination with docetaxel (4.38 nM) synergistically reversed docetaxel resistance of DTR-143B cells resulting in 73.7% inhibition of cell growth compared to docetaxel alone (7.3%), a 10-fold increase in docetaxel efficacy, or rMETase alone (54.6%) (p<0.05) (Figure 3).

Figure 3.
Figure 3.

Efficacy of docetaxel, recombinant methioninase (rMETase) and their combination on docetaxel-resistant 143B (DTR-143B) cells. Control (DMEM); docetaxel (4.38 nM); rMETase (0.53 U/ml); docetaxel (4.38 nM) plus rMETase (0.53 U/ml); n=3, *p<0.05.

Discussion

Docetaxel is used in combination with gemcitabine for second-line treatment of recurrent or refractory osteosarcoma (2). In a phase II study of docetaxel for recurrent osteosarcoma, all 14 patients died from progressive disease, with a median survival time of 8 months from the initiation of docetaxel chemotherapy (ranging from 1 to 20 months) (19). The present results demonstrated rMETase increased the efficacy of docetaxel on DTR-143B osteosarcoma cells 10-fold, suggesting clinical promise to this recalcitrant disease.

We have previously shown that oral-rMETase (o-rMETase) sensitized a patient-derived orthotopic xenograft (PDOX) model of osteosarcoma to docetaxel (20). We have also recently shown that rMETase sensitized prostate cancer cells to docetaxel (21). In the present study, the combination of rMETase and docetaxel resulted in a 10-fold increase of efficacy on DTR-143B cells compared to docetaxel alone.

We have previously shown that rMETase sensitized osteosarcoma to methotrexate, docetaxel and cisplatinum (20, 22, 23), and sensitized soft tissue sarcoma to doxorubicin (24-30). We have also recently shown that rMETase sensitized drug-resistant soft-tissue sarcoma cells to eribulin, trabectedin and doxorubicin (15, 31, 32).

Synergy of methionine restriction, including rMETase, and chemotherapy is due at least in part to the selective late-S/G2 cell-cycle arrest of cancer cells during methionine restriction (33-35).

rMETase is effective because it targets the fundamental hallmark of cancer, methionine addiction, termed the Hoffman effect (6, 7, 36-57).

The present results suggest that rMETase in combination with docetaxel has clinical potential for osteosarcoma patients who have developed docetaxel resistance as o-rMETase is showing clinical promise (11, 58-66).

Acknowledgements

This article is dedicated to the memory of A.R. Moossa, MD, Sun Lee, MD, Professor Gordon H. Sato, Professor Li Jiaxi, Masaki Kitajima, MD, Joseph R. Bertino, MD, Shigeo Yagi, PhD, J.A.R Mead, Ph.D., Eugene P. Frenkel, MD, Professor Lev Bergelson, Professor Sheldon Penman, Professor John R. Raper, Joseph Leighton, MD and John Mendelsohn, MD. The Robert M. Hoffman Foundation for Cancer Research provided funds for the present study.

Footnotes

  • Authors’ Contributions

    SM, RMH, and QH designed the study. QH provided rMETase. SM performed experiments. SM was the major contributor to writing the article and RMH revised the article. KM, BMK, MS, MB, NY, KH, HK, SM, KI, TH, HT, and SD critically read the manuscript.

  • Conflicts of Interest

    The Authors have declared that there are no competing interests in relation to this study.

  • Received August 23, 2024.
  • Revision received September 7, 2024.
  • Accepted September 9, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Recombinant Methioninase Synergistically Reverses High-docetaxel Resistance Developed in Osteosarcoma Cells
SEI MORINAGA, QINGHONG HAN, KOHEI MIZUTA, BYUNG M. KANG, MICHAEL BOUVET, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, HIROYUKI TSUCHIYA, SATORU DEMURA, ROBERT M. HOFFMAN
Anticancer Research Nov 2024, 44 (11) 4773-4778; DOI: 10.21873/anticanres.17303
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